Metabolic dysfunction-associated steatotic liver disease and diabetes: Together against the heart

Type 2 diabetes mellitus (T2DM) is a modifiable risk factor both for atrial fibrillation (AF) and for the development of cerebrovascular-events in patients with AF. The aim of our study was to determine the effect of cryoballoon ablation (CBA) treatment on long-term atrial-tachyarrhythmia recurrence and adverse cardiovascular (CV) events in paroxysmal AF patients with T2DM. This retrospective-observational-cohort study included 748-patients (406-male,342-female,59.4 ± 11.8years) who underwent CBA with a diagnosis of paroxysmal AF between 2013-2023. The primary endpoint was atrial tachyarrhythmia recurrence (After-CBA≥3months) and the secondary endpoint was development of CV-events (CV mortality, non-fatal myocardial infarction and cerebrovascular-events). All patients were followed up for at least 24 months for atrial-tachyarrhythmia recurrence and CV event development. The prevalence of T2DM was 26% in patients who underwent CBA. Atrial-tachyarrhythmia recurrence and CV events were more frequent in the T2DM group (24%vs15%,p = 0.004 and 33%vs9%,p = 0.045, respectively). Systolic-diastolic blood pressure, female gender, frequency of T2DM and anti-diabetic drug use, and left atrial diameter (LAd) values were higher in patients with atrial-tachyarrhythmia recurrence (p < 0.05). The presence of LAd and T2DM were shown to independently predict the development of atrial-tachyarrhythmia recurrence (OR = 1.235,95%CI-1.169-1.305, p < 0.001andOR = 1.843,95%CI-1.116-3.406,p = 0.030). Male-gender and presence of T2DM, CHA2DS2-VA score and uric-acid were shown to independently predict CV events (OR = 1.906,95%CI1.102-3.299,p = 0.021,OR = 2.148,95%CI-1.073-4.303,p = 0.013,OR = 1.613,95%CI-1.346-1.932,p = 0.001andOR = 1.322,95%CI-1.125-1.554,p = 0.001). The presence of T2DM is an important, independent and modifiable risk factor for both atrial-tachyarrhythmia recurrence and adverse CV events in patients treated with CBA for AF. It was concluded that comprehensive management of T2DM is necessary to improve long-term outcomes of CBA.

Cystatin C is an established biomarker for renal function, and, given the close association of chronic kidney disease and cardiovascular disease might indicate new-onset or deteriorating cardiovascular disease. However, evidence for cystatin C as a predictor of cardiovascular events is limited and controversial. We therefore aimed at investigating the role of cystatin C as a predictor of future cardiovascular events in a high risk-cohort of patients with established coronary artery disease (CAD). We prospectively recorded cardiovascular events in 1053 patients with angiographically verified CAD over a mean follow-up of 9.5±5.3 years. At baseline, 352 patients had type 2 diabetes mellitus (T2DM) and 701 did not have T2DM. During follow-up, 560 (53.2%) of our patients suffered cardiovascular events. Cystatin C proved to be a strong and independent predictor for cardiovascular events in the total study cohort (standardized adjusted HR 1.22 [1.12-1.33], p&amp;lt;0.001). When T2DM status was taken into account, cystatin C significantly predicted cardiovascular events both in patients with T2DM (HR 1.18 [1.04-1.35], p=0.011) and in nondiabetic patients (HR 1.23 [1.09-1.38], p&amp;lt;0.001). We conclude that cystatin C predicts cardiovascular events in CAD patients both among those with and among those without T2DM. Disclosure T. Plattner: None. B. Larcher: None. A. Mader: None. A. Vonbank: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.

Treatment of type 2 diabetes mellitus (T2DM) patients with pioglitazone results in a more favorable lipid profile, and perhaps more favorable cardiac outcomes, than treatment with rosiglitazone. Pioglitazone treatment increases VLDL-triacylglycerol clearance, but the role of de novo lipogenesis (DNL) has not been explored, and no direct comparison has been made between the thiazolidinediones (TZDs). Twelve subjects with T2DM and hypertriacylglyceridemia were randomized to either rosiglitazone or pioglitazone treatment. Stable isotope infusion studies were performed at baseline and after 20 weeks of treatment. Both treatments reduced glucose and HbA(1c) concentrations equally. Pioglitazone treatment resulted in a 40% reduction in hepatic DNL (P < 0.01) and in a 25% reduction in hepatic glucose production (P < 0.05), while rosiglitazone did not significantly change either parameter, although comparisons of changes between treatments were not significantly different. These pilot results indicate that pioglitazone reduces hepatic DNL while rosiglitazone does not. Larger follow-up studies are required to confirm differential effects of these agents definitively. The reduction in DNL may underlie altered assembly or atherogenicity of lipoprotein particles and may reflect PPARalpha or other non-PPARgamma actions on the liver by pioglitazone. These differences might help explain previously reported differences in lipid profiles and cardiovascular disease outcomes for rosiglitazone and pioglitazone.

The Visceral Adiposity Index (VAI) is calculated based on waist circumference, BMI, triglyceride and HDL-cholesterol levels and is a validated measure of visceral adiposity. In the general population, the VAI has been shown to be an independent risk factor for premature mortality. Its power to predict cardiovascular events in patients with coronary artery disease (CAD) with or without type 2 diabetes mellitus (T2DM) is not known and is addressed in the present study. We prospectively investigated 927 patients with angiographically diagnosed CAD over a mean follow-up time of 8.2±4.3 years. At baseline, the VAI was significantly higher in patients with T2DM (n=303) than in those who did not have diabetes (6.5±5.2 vs. 4.8±4.9; p&amp;lt;0.001). During follow-up, we recorded 385 cardiovascular events. The VAI significantly predicted the incidence of cardiovascular events both univariately (standardized HR 1.09 [1.02-1.16]; p=0.011) and after adjustment for age, gender, smoking, LDL cholesterol, hypertension and T2DM (standardized adjusted HR 1.11 [1.04-1.18]; p=0.002); also T2DM significantly predicted cardiovascular events in this fully adjusted model (adjusted HR 1.26 [1.04-1.52]; p=0.018) independently from the VAI. We conclude that the VAI and T2DM are mutually independent predictors of cardiovascular events in patients with CAD. Disclosure T. Plattner: None. B. Larcher: None. A. Mader: None. A. Vonbank: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.

NAFLD is commonly associated with Type 2 diabetes mellitus in clinical practice it is overlooked despite the significant clinical implications of NAFLD in Type 2 diabetes mellitus. Non-Alcoholic Fatty Liver Disease (NAFLD) in association with Type 2 Diabetes Mellitus (T2DM) can significantly increase the risk and severity of both conditions. Peripheral insulin resistance serves as a central mechanism in the pathogenesis of NAFLD and T2DM alike. The estimated prevalence of NAFLD in individuals with T2DM ranges from 70% to 75%. Patients diagnosed with both NAFLD and T2DM tend to have a poorer prognosis, with the mortality rate due to cirrhosis being notably higher in diabetic patients compared to the general population. This study was done to estimate the prevalence of NAFLD in diabetes mellitus. The term MASLD formally MAFLD will now be MASLD (Metabolic dysfunction - associated steatotic liver disease [51] MAFLD was defined as the presence of SLD with overweight/obesity (BMI &gt; 25 kg/m2), T2DM or presence of metabolic dysregulation. MASLD was defined as SLD with atleast one cardiometabolic risk factor without excessive alcohol intake [51]. This new nomenclature defined by multisociety Delphi process and proposed by a panel of expert will help to differentiate people with pure MASLD from those MetALD (Metabolic liver disease associated with alcohol [51]. Methods: This cross-sectional observational study was conducted in both the outpatient and inpatient settings of the Department of General Medicine at Al-Ameen Medical College Hospital, Vijayapura, over a period of 18 month (July 2023 to December 2024). A total of 96 patients diagnosed with Type 2 Diabetes Mellitus (T2DM) or Type 1 DM on insulin therapy, who met the inclusion and exclusion criteria, were enrolled in the study. The inclusion criteria were based on the American Diabetes Association (ADA) guidelines¹⁸, which define diabetes as a fasting plasma glucose level of ≥126 mg/dL, a 2-hour postprandial blood glucose level of ≥200 mg/dL, or an HbA1C level of ≥6.5%. Patients were excluded if they had a history of alcohol consumption, tested positive for HIV, HCV, or HBsAg, or were on medications known to cause steatohepatitis, such as steroids, methotrexate, and estrogen-containing preparations. The sample size (n = 96) was obtained using Statulator software, based on an anticipated prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) among diabetic patients of 51.3%¹⁷, with a 95% confidence level and 10% absolute precision. Results: In our study of 96 diabetic patients, the majority (38.5%) were aged 21–40 years, with no significant age or gender differences (male-to-female ratio: 1.08:1). The overall prevalence of MASLD was 51.0%, with no statistically significant gender association. Obesity was significantly more common in MASLD patients (52.0%) than non-MASLD patients (19.7%) (P &lt; 0.01), and BMI was significantly higher in the MASLD group. Central obesity markers, including waist circumference and waist-hip ratio, showed strong associations with MASLD in both males and females (P &lt; 0.001). Additionally, liver enzymes (SGOT, SGPT, ALP) were significantly elevated in MASLD patients (40.8%) compared to non-MASLD patients (12.7%) (P &lt; 0.01), highlighting their potential diagnostic value. Conclusion: MASLD is highly prevalent among diabetic patients, with obesity and dyslipidemia identified as major contributing factors, and liver function tests proving useful for early diagnosis. The study highlights the significance of metabolic parameters such as BMI, waist circumference, and lipid profile in the development of MASLD and supports existing evidence that MASLD independently contributes to liver dysfunction and metabolic complications in diabetics. Although no statistically significant gender difference in MASLD prevalence was observed, male patients demonstrated a higher tendency toward central obesity and associated metabolic changes. These findings underscore the importance of early screening and timely intervention to prevent the progression of MASLD in individuals with diabetes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing cause of cirrhosis and its complications. Given its close association with type 2 diabetes mellitus (T2DM), evaluating whether sodium-glucose cotransporter-2 inhibitors (SGLT2is) can mitigate the progression of liver fibrosis is clinically important. We examined the association between SGLT2i use and liver fibrosis progression in patients diagnosed with MASLD and T2DM. We conducted a target trial emulation study using a retrospective, active comparator new-user design among adults with MASLD, T2DM, and low-to-intermediate Fibrosis-4 (FIB-4≤2.67) scores who initiated treatment with either SGLT2is or dipeptidyl peptidase-4 inhibitors (DPP-4is) at Mass General Brigham or Asan Medical Center from 2013 to 2023. The primary outcome was the progression to advanced fibrosis (FIB-4>2.67), confirmed on ≥2 occasions within 1 year. The secondary outcome was the development of major adverse liver outcomes (MALO), including incident cirrhosis, decompensation events, hepatocellular carcinoma, or liver transplantation. Among 16,901 eligible patients, 2,571 propensity score-matched pairs were identified with balanced baseline characteristics. During follow-up (median, 3.7 years), fibrosis progression occurred at a rate of 3.46/100 personyears in SGLT2i users and 4.44 in DPP4i users. SGLT2i use was associated with a lower risk of fibrosis progression (HR 0.78, 95% CI 0.67-0.89; P<0.001). No significant difference in MALO incidence was observed. Subgroup analyses showed a consistent association among users of metformin, statins, and aspirin. SGLT2i use was associated with reduced risk of fibrotic progression compared to DPP4i use in adults with MASLD and T2DM.

This study aims to examine the impact of the association between metabolic syndrome (MetS) and metabolic dysfunction-associated fatty liver disease (MAFLD) , which both have insulin resistance and are pathophysiologically similar, on the development of new-onset cardiovascular disease, with and without type 2 diabetes mellitus (T2DM) A total of 570,426 participants without a history of cardiovascular disease who were enrolled in the nationwide claims database from 2008-2016 were included in this study. Participants were classified according to the presence or absence of MetS and/or MAFLD, and the risk of developing coronary artery disease (CAD) and/or cerebrovascular disease (CVD) in each category was analyzed using a multivariate Cox proportional hazard model. The same analysis was performed with stratification by the presence or absence of T2DM. During a median follow-up of 5.2 years, 2,252 CAD and 3,128 CVD events occurred. The hazard ratio (HR) (95% CI) for CAD, compared with the group with neither MAFLD nor MetS, was 1.46 (1.32-1.62) for MAFLD only (without MetS) , 2.02 (1.51-2.70) for MetS only (without MAFLD) , and 2.33 (2.10-2. 58) for MAFLD + MetS. For CVD, The HR was 1.41 (1.28-1.55) for MAFLD only, 1.67 (1.38-2.02) for MetS only, and 1.89 (1.72-2.08) for MAFLD + MetS. These results were similar for non-T2DM participants but different for T2DM participants, with no significant increased risk for CAD in MetS only and a significant increased risk for CVD only when both MAFLD and MetS coexisted. The predictive ability for cardiovascular disease development in patients with MetS and MAFLD differed depending on the presence or absence of T2DM. These results suggest that distinguishing between the diagnosis of MetS and MAFLD, taking into account the presence or absence of T2DM, may lead to more accurate identification of patients at high risk of developing cardiovascular disease. Disclosure K. Fujihara: None. M.H. Yamada: None. M. Yamamoto: None. H. Ishiguro: None. M. Kitazawa: None. M. Iwanaga: None. S. Kodama: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. Funding The Japan Society for Promotion of Science (JSPS) KAKENHI Grant Number JP 20K19706)

Clinical trials of glucose-lowering strategies in patients with type 2 diabetes mellitus (T2DM) have shown a favorable effect of intensive glycemic control on microvascular complications but failed to show a clear benefit on cardiovascular events. In 2008, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have required stringent criteria to approve new glucose-lowering drugs, demanding proof of cardiovascular safety. As a result of these regulatory requirements, a number of cardiovascular outcome trials in T2DM have been conducted examining the cardiovascular safety of novel glucose-lowering drugs. Dipeptidyl peptidase 4 (DPP4) inhibitors, analogs of glucagon-like peptide 1 (GLP-1), and inhibitors of the renal sodium-glucose linked transporter-2 (SGLT2) are new classes of glucose-lowering drugs for subjects with T2DM. The results of the cardiovascular outcome trials comparing the DPP4 inhibitors saxagliptin, alogliptin, and sitagliptin or the GLP-1 analog lixisenatide to placebo have demonstrated that these drugs are safe. The results of a cardiovascular outcome trial comparing the SGLT2 inhibitor empagliflozin to placebo have been published. Notably, empagliflozin treatment has been associated with a significant reduction in the primary composite cardiovascular outcome. Although the question regarding the positive effect of glycemic control on cardiovascular risk is still unanswered, current evidence suggests that a multifactorial approach aimed at treating not only hyperglycemia but also classical cardiovascular risk factors is necessary in order to reduce the risk of cardiovascular events in patients with T2DM.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in individuals with type 2 diabetes mellitus (T2DM). MASLD carries a substantial risk of progression to cirrhosis or hepatocellular carcinoma (HCC). Whether the metabolic benefits of antidiabetic therapy may alter this progression remains under-investigated. We aimed to evaluate the incidence of cirrhosis or HCC across the commonly used second-line antidiabetic agent classes in patients with coexisting MASLD and T2DM. We conducted a retrospective cohort study using healthcare claims databases in the United States. Patients with MASLD and T2DM initiating one of the three antidiabetic agent classes, glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and dipeptidyl peptidase-4 inhibitors (DPP-4i) were included. Propensity score (PS) matching was applied to control for baseline differences between treatment groups. Cumulative incidence of cirrhosis or HCC over 2 years was estimated with Kaplan-Meier method, and risks between treatment groups were compared using Cox regression. The analysis included three PS-matched cohorts: 4538 GLP-1RA versus DPP-4i pairs, 4754 SGLT2i versus GLP-1RA pairs, and 4333 SGLT2i versus DPP-4i pairs. In the intention-to-treat analysis, no statistically significant differences in the risk of cirrhosis or HCC were observed at 2 years across treatment comparisons (GLP-1RA vs. DPP-4i: hazard ratios [HR] 0.80, 95% confidence intervals [CI] 0.58-1.09; GLP-1RA vs. SGLT2i: HR 0.76, 95% CI 0.55-1.04; SGLT2i vs. DPP-4i: HR 0.78, 95% CI 0.58-1.05). In this large real-world study, we found no clear or consistent differences in liver-related outcomes across GLP-1RA, SGLT2i, and DPP-4i users over a 2-year period.

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) constitutes a significant cause of chronic liver disease globally. Type 2 diabetes mellitus (T2DM) is a crucial risk factor for MASLD. This investigation is aimed at assessing hepatic fibrosis in T2DM patients with MASLD. Methods This cross-sectional study focused on T2DM patients with MASLD attending a tertiary care center in eastern India. Exclusion criteria were chronic alcohol intake (more than 21 units/week for males and more than 14 units/week for females), other chronic liver diseases, and pregnancy. The study utilized abdominal ultrasonography and transient elastography, complemented by calculating the BARD score, nonalcoholic fatty liver disease (NAFLD) fibrosis score, aspartate aminotransferase to platelet ratio index (APRI) score, and fibrosis 4 (FIB-4) index. The prevalence of advanced fibrosis in patients with T2DM and MASLD was assessed using transient elastography. Results Among the 149 T2DM patients with MASLD studied, 59.7% were female, with an average age of 49.09 years and a T2DM duration of 7.3 years. Transaminitis was detected in 9.4% of the subjects. The risk assessment of hepatic fibrosis revealed that 14.1% of patients had a high risk of hepatic fibrosis on BARD scoring, the NAFLD fibrosis score was in the range of F3-F4 in 8.7% of patients, the FIB-4 index showed a high risk of fibrosis in 5.4% of patients, and the APRI scoring showed severe fibrosis in 3.4% of patients.The prevalence of advanced fibrosis in patients with T2DM and MASLD was 7.4% (95% confidence interval (CI) 3.7 to 12.8), while 75.8% (95% CI 68.2 to 82.5) of participants had at least some level of hepatic fibrosis as measured by transient elastography.Notably, there was a significant positive correlation between these scores and the duration of diabetes and serum bilirubin levels, as corroborated by concordant transient elastography findings. On multivariate logistic regression, systolic blood pressure, serum total bilirubin level, and serum aspartate aminotransferase level had significant predictive value for advanced hepatic fibrosis. Conclusion The significant predictive value of systolic blood pressure, serum total bilirubin level, and serum aspartate aminotransferase level for hepatic fibrosis emphasizes the importance of integrated monitoring for these patients.

Background:Epicardial adipose tissue (EAT) is an indicator of high cardiovascular and metabolic risk. This study aimed to investigate the association between EAT thickness (EATT) and liver fibrosis and steatosis in patients with type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD).Methods:Patients with T2DM and MASLD underwent a complex evaluation, which included clinical, laboratory, and liver and transthoracic cardiac ultrasound assessments. The EATT was measured using the standard method. Liver fibrosis and steatosis were evaluated by several non-invasive indexes, through which patients with severe steatosis and advanced fibrosis were identified. Correlations between the EATT and markers of liver fibrosis and steatosis were evaluated by bivariate and multiple regression analyses.Results:In this study population of 267 T2DM patients with MASLD, the median EATT value was 7 mm. 43.8% of study patients had an EATT >7 mm. The EATT was higher in patients with advanced liver fibrosis (8.97 ± 2.88 mm vs. 7.09 ± 2.38 mm; p < 0.0001) and in those with more severe hepatic steatosis (7.69 ± 2.70 mm vs. 6.61 ± 1.88 mm; p = 0.0310). A higher percentage of patients with advanced liver fibrosis had an EATT of >7 mm (68.3% vs. 36.7%; odds ratio (OR) = 3.72 [95% confidence interval (CI): 2.02; 6.87]; p < 0.0001). In the bivariate analyses, the EATT significantly correlated with the markers of body adiposity, non-invasive indexes of liver steatosis and fibrosis, aspartate aminotransferase (ASAT), gamma glutamyl transpeptidase (GGT), diabetes duration, and pO2. The multiple regression analyses indicated that the EATT was independently associated with fibrosis-4 (FIB-4) score and body fat mass, and with serum ferritin (in fully adjusted models), while the correlation with the markers of hepatic steatosis became non-significant after adjustments for body adiposity.Conclusion:T2DM patients with MASLD and markers of advanced liver fibrosis have higher EATT, which was independently associated with liver fibrosis.

Waist Circumference and Insulin Resistance Are the Most Predictive Metabolic Factors for Steatosis and Fibrosis

BackgroundThe frequency of type 2 diabetes mellitus (T2DM) is rising annually. Coronary heart disease (CHD) is a prevalent complication affecting individuals with T2DM.ObjectiveThe aim of this investigation was to assess the level of DBH-AS1 in T2DM with CHD, and to determine its potential role in forecasting the occurrence of significant cardiovascular events.MethodsThe DBH-AS1 levels were detected by qRT-PCR. The diagnostic value of DBH-AS1 was assessed through receiver operating characteristic (ROC) curve analysis. Logistic regression was conducted to identify the risk factors for cardiovascular events among patients with T2DM with CHD. Cell proliferation was detected by Cell Counting Kit-8 (CCK-8) assay, apoptosis was detected by flow cytometry, and the concentration of inflammatory factors was detected by Enzyme Linked Immunosorbent (ELISA) kit.ResultsDBH-AS1 was down-regulated in serum of both T2DM with CHD and cardiovascular events patients. Of the cardiovascular events that occurred, major events included recurrent angina (20%), cardiovascular death (7.5%), acute myocardial infarction (23.75%), severe arrhythmia (22.50%), acute heart failure (18.75%) and stroke (7.5%). And DBH-AS1 had a predictive value for each adverse of cardiovascular events. DBH-AS1 regulated the expression of miR-483-5p and affected the proliferation, apoptosis, and secretion of inflammatory factors of HCAECs.ConclusionDBH-AS1 may serve as a predictor for the occurrence of cardiovascular events in T2DM with CHD patients.

Treatment Strategy for Type 2 Diabetes with Obesity: Focus on Glucagon-like Peptide-1 Receptor Agonists

PurposeTo identify the characteristics and initial disease severity of patients with nonalcoholic fatty liver disease (NAFLD) and assess incidence and risk factors for disease progression in a retrospective study.MethodsPatients ≥18 years of age without alcoholism or other liver diseases (eg, hepatitis B/C) were selected from Geisinger Health System electronic medical record data from 2004 to 2015. Initial disease stage was stratified into uncomplicated NAFLD, advanced fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and liver transplant using clinical biomarkers, diagnosis, and procedure codes. Disease progression was defined as stage progression or death and analyzed via Kaplan–Meier plots and multistate models.ResultsIn the NAFLD cohort (N=18,754), 61.5% were women, 39.0% had type 2 diabetes mellitus (T2DM), and the mean body mass index was 38.2±10.2 kg/m2. At index, 69.9% had uncomplicated NAFLD, 11.7% had advanced fibrosis, and 17.8% had cirrhosis. Of 18,718 patients assessed for progression, 17.3% progressed (11.0% had stage progression, 6.3% died without evidence of stage progression) during follow-up (median=842 days). Among subgroups, 12.3% of those without diabetes mellitus progressed vs 24.7% of those with T2DM. One-year mortality increased from 0.5% in uncomplicated NAFLD to 22.7% in HCC. After liver transplant, mortality decreased to 5.6% per year.ConclusionsIn 2.3 years of follow-up, approximately 17% of patients progressed or died without evidence of stage progression. T2DM was associated with approximately twice the risk of disease progression, and mortality risk increased with disease stage. Early diagnosis and monitoring of disease progression, especially in patients with T2DM, is warranted.